RANK ligand: effects of inhibition.

Receptor activator of nuclear factor kappa-light-chain-enhancer of activated B-cells (RANK) and its ligand (RANKL) belong to the tumor necrosis factor (TNF) superfamily. RANK mRNA is expressed widely in bone and bone marrow. It has a significant role in stimulating osteoclast differentiation and maturation, and also in preventing apoptosis. Because osteoclast activity is an important aspect of bone resorption in malignancy, targeting these cells is a good rationale for preventing skeletal-related events in malignancies. Preclinical studies have demonstrated the efficacy of denosumab in preventing bone loss in mice and improving bone mineral density. Denosumab is a fully human monoclonal antibody against RANKL, which has been shown to be effective in reducing signaling via RANK and thus osteoclast activity. It has been demonstrated in large, randomized, phase 3 studies to be effective in preventing fractures and bone loss, and improving the bone mineral density in various cancerous and noncancerous settings. This article reviews the latest evidence of RANKL inhibition and its clinical implications.